We also recommend higher-than-typical dietary intakes of zinc and copper, key ingredients of the antioxidant zinc-copper superoxide dismutase.

We recommend high intakes of extracellular matrix material in soups and stews. This is rich in glycine, a component of glutathione, a key antioxidant. N-acetylcysteine, which provides the other amino acid component of glutathione, is one of our therapeutic supplements.

Although we don’t normally recommend supplementing vitamin E, it is listed among our optional supplements, and we believe significant numbers of people might benefit from supplementing mixed tocotrienols.

Although we don’t recommend supplementing it, our book notes the importance of dietary intake of selenium, which is critical for an enzyme that recycles glutathione.

A fashionable contrary view has arisen: antioxidants not only don’t help, they can do harm by interfering with oxidative signaling pathways.

The Bjørnsen Study: Muscle Size

In this new study, Bjørnsen and collaborators put a group of elderly men on a strength training regimen. Half the men were put on supplements – 1000 mg per day of vitamin C and 235 mg (350 IU) per day of the alpha-tocopherol form of vitamin E – and half on placebo. They then assessed the response to 12 weeks of exercise.

Both groups gained muscle mass, but the placebo group gained more. Total lean mass, and the thickness of the rectus femoris muscle (one of the quadriceps), increased more in the placebo than the antioxidant group. The lean mass increase averaged 3.9% in the placebo group, 1.4% in the antioxidant group. Here’s the plot of muscle thickness in the rectus femoris:

This muscle increased in thickness an average of 16.2% in the placebo group, 10.9% in the antioxidant group.

So far, so solid: it looks like muscle size will be larger if you don’t take antioxidants.

Adel concludes:

[Y]ou shouldn’t fall for … the bogus false promise that suffocating all the flames by using exorbitant amounts of antioxidants (and I am as this study shows talking about 10x the RDA not just 100x the RDA) would be good for you, let alone your training progress and muscle gains…. [Y]ou cannot recommend extra-vitamins for people who work out – specifically not the elderly.

I disagree.

The Trouble with Biomarkers

We have to use biomarkers to assess health, because the things we really care about – like how long we will live – cannot be determined on the time scales we need to make decisions in.

But no biomarker is a perfect assessment of health. There are always regimes in which a biomarker can look “better” but health can worsen.

Muscle size is no different. Other things being equal, more muscle is better than less muscle. But there are ways to increase muscle size that harm health. We have to look at the increase in muscle size in the placebo group and ask: was this good or bad?

The Bjørnsen Study: Strength

Fortunately, Bjørnsen and colleagues also reported another key biomarker: strength, as indicated by 1 rep maximum weight. Here is the data:

The exercises that utilize the rectus femoris muscle, the one that grew biggest in the placebo group, are the leg extension (b) and leg press (c). And here we see something interesting: in both cases, the antioxidant group increased their 1RM by more than the placebo group. Yes, the improvement was not statistically significant. But it was there. According to the text, on average, the antioxidant group increased their leg press 1RM by 18.7%, the placebo group by 15.8%.

So the antioxidant group gained more strength but less size than the placebo group. Which group was made healthier by the program?

I’ll put my money down on this: the smaller muscle that can exert more force is the healthier muscle. A gargantuan but weak muscle is an unhealthy muscle.

Large Muscle Size Can Be a Sign of Poor Health

To see that large muscles may be unhealthy, consider the health condition of cardiomegaly – an enlarged heart. When the heart tissue is dysfunctional and incapable of exerting as much strength as it should, the heart grows larger to compensate. People who have such an oversized but weak heart often die an early death.

We should consider whether something similar was going on in the placebo group of the Bjørnsen study. Their leg muscles grew larger to compensate for weakness. They needed more mass to accomplish less than the antioxidant group.

What causes cardiomegaly? One contributing factor is a deficiency of antioxidants. When antioxidants are deficient, oxidative stress generated during exertion leads to lipid peroxidation and tissue necrosis.

One of my favorite nutritional studies – I always show it at the Perfect Health Retreat to demonstrate the existence of multi-nutrient deficiency diseases, diseases that appear only when you are deficient in multiple nutrients at the same time – is a study by Kristina Hill and collaborators at Vanderbilt in 2001. [2] The running title is “Myopathy resulting from combined Se and E deficiency” and that summarizes it well. Guinea pigs were put on one of four diets – a control diet, the control diet but deficient in vitamin E, the control diet but deficient in selenium, or the control diet with both vitamin E and selenium removed.

Something interesting happened to the guinea pig muscles:

These are quadriceps muscles – the same muscle whose size was altered in the Bjørnsen study. Panel (D) shows a healthy muscle from the control group. The muscle fibers are long, straight, and parallel to one another. Panels (B) and (C), the low vitamin E and low selenium groups respectively, are mildly damaged but still functional. However, in panel (A), the group deprived of both selenium and vitamin E, the muscle fibers are severely damaged. This muscle cannot exert force.

In the group deprived of both selenium and vitamin E, the loss of strength continued until the guinea pigs could no longer stand or move. At that point they lost the ability to feed and began to die of starvation. This happened in as little as 30 days. Here was the survival curve:

The last guinea pig died after 55 days.

Why did this happen? The guinea pig muscles were damaged by lipid peroxidation leading to cell death. They didn’t have enough antioxidants.

Hill et al didn’t measure muscle thickness, but it wouldn’t surprise me if at 20 days the guinea pigs on their way to an early death had the thickest and most massive quadriceps.

Can Muscle Size Be Used as an Indicator of Overtraining?

If growth in muscle size may indicate muscle damage from either overtraining or antioxidant deficiencies, we might be able to use the response to exercise to assess nutrition or exercise load.

Let’s look again at the Bjørnsen study. If the cross-sectional area of a muscle is proportional to the square of muscle thickness, then we can get a measure of strength per unit cross-section by taking the ratio of leg press 1RM to the square of rectus femoris thickness. That is 1.187/1.109^2 = 0.965 in the antioxidant group, 1.158/1.162^2 = 0.857 in the placebo group. Per unit cross-section, the antioxidant group lost 3.5% in strength, the placebo group lost 14.3%.

It looks like both groups may have damaged their muscles; the antioxidant group just did much less damage. It appears both groups were overtraining relative to their nutritional status. Perhaps if nutrition were better, the response to exercise would have been better, and strength per unit cross-section would have increased. Maybe the missing nutrients included antioxidants, and taking even more antioxidants may have enabled this rigorous training regimen (designed “to stimulate as much muscle growth as possible”) to take place without any impairment of health.

Is Bodybuilding Safe?

If large size can be an indication of damage in muscle, then many techniques which cause muscular hypertrophy will be health-damaging. The healthiest strength gains might come with only small size gains, as the muscle becomes more efficient. It is only unhealthy muscle that becomes super large.

If so, then bodybuilders, who are judged on the size of their muscles, not their strength, will be tempted to use health-damaging and muscle-damaging techniques, like antioxidant deficiencies, to expand their muscle mass. Presumably the winning bodybuilders will be those who use all effective techniques to grow muscle, including the health-damaging ones. So we should expect champion bodybuilders to die young.

I have not seen statistical evidence, but anecdotal lore suggests that champion bodybuilders do, indeed, die young, often of heart diseases (indicating muscle damage). Here are two Youtube videos memorializing bodybuilders who died young:

Conclusion

If you want me to believe that antioxidants are bad, the Bjørnsen study is not going to do it. It looks to me that the elderly men who were in the antioxidant group were the lucky ones. The 1000 mg of vitamin C and 350 IU of vitamin E they were taking daily improved their response to exercise. Indeed, for all we know their antioxidant intake may have been less than optimal!

The elderly men who didn’t get the antioxidants should worry about their hearts. If their leg muscles became large but weak, their hearts may have also.

Everyone who works out should be aware: when it comes to muscles, bigger is not the same as better. The healthiest muscles are those in a wiry physique – modest size, but able to exert a lot of force.

Finally, a pitch for our upcoming October 10-17 Perfect Health Retreat. Our advice is sensible, comprehensive, and increasingly well supported by guest experience. If you want to learn how to optimize health for the rest of your life, and have a great time doing it, please come join us.

Our May Perfect Health Retreat begins on Saturday, and we’re thrilled to announce a new partner: AOBiome.

In January I blogged (“UBiome and the May 2015 Perfect Health Retreat”) about our partnership with uBiome.com. UBiome has contributed two gut microbiome sequencing kits for each guest, and we’re sequencing gut microbiomes pre-retreat and at the end of the retreat to see if a week together in a PHD-optimized environment causes microbiomes to converge to a “Perfect Health Diet” pattern.

Now, AOBiome is donating a four week supply of their AO+Mist skin probiotic to each guest. To see why I’m excited about this, I have to say a little about nitric oxide.

Nitric Oxide and Health

Nitric oxide is a gaseous signaling molecule with powerful effects on blood vessels, nerves, the immune system, gut and skin. It has proven to be such an important molecule that the three pharmacologists who established its role in relaxing blood vessels were awarded the Nobel Prize for Medicine in 1998.

Nitroglycerin, the explosive which turned out to be an effective remedy for heart failure, works by increasing nitric oxide levels.

How do we obtain nitric oxide? It is a gas so you can’t eat it. Rather, we eat green leafy vegetables and beets to obtain nitrates; nitrates and bacteria-generated derivatives like nitrites are stored in the body, especially the skin; and then sunshine on the skin, among other processes, generates NO.

Here is dermatologist Richard Weller explaining why nitric oxide may be the reason sunshine is so good for our hearts, and why Scotsmen die so young despite the benefits of malt whisky:

Ammonia-Oxidizing Bacteria

Unfortunately, most of us don’t eat enough spinach to optimize our nitrate status. It would be wonderful if there were another way to obtain nitric oxide precursors.

David Whitlock, the scientist-founder of AOBiome, realized that there is. He was wondering why horses and other animals wallow in the mud, and realized that they might be obtaining probiotic bacteria for the skin from the soil.

Investigation revealed that a class of bacteria called ammonia-oxidizing bacteria are present in soil and, when they colonize the skin, can transform ammonia excreted in sweat to nitrite which can be re-absorbed by the body. These “AOBs” not only improve nitric oxide status, they improve body odor by eliminating ammonia. But they are destroyed by soaps and chlorinated water. Since most people use soap, take chlorinated showers, and rarely wallow naked in the mud, we lack these AOBs.

So AOBiome came up with the idea of a skin probiotic – some AOBs dissolved in water that you spritz on your skin after a morning shower, to re-colonize your skin each morning.

Thank You, AOBiome

The Perfect Health Retreats represent our best effort to develop natural ancestral healing methods based on diet, lifestyle, and a healthful environment. Microbes are an important part of our environment, and managing our microbial environment has the potential to significantly improve health.

AO+Mist has not been tested in clinical trials, and there is no direct evidence that it will be beneficial to health. But the mechanisms seem logical, and I’m delighted that our guests will have a way to obtain ammonia-oxidizing skin bacteria without nakedness or mud. Thank you, AOBiome!

You don’t have to attend the retreat to benefit from AOBiome’s generosity. For readers of our blog, AOBiome is offering a 25% discount. Go here to purchase AO+Mist and use the coupon code phd25 for your discount.

A lot of people have asked about the Atlantic article by Paul Offit, “The Vitamin Myth: Why We Think We Need Supplements.” Offit, a pediatrician, is best known for his defense of childhood immunizations. In arguing against benefits from vitamins, as he did in arguing against harm from vaccines, he takes a strong stand.

Before I take a look at his article, let me mention a competing publication about supplements that became available today, and might be more worthy of your time.

Examine.com’s Supplement Goals Reference Guide

A friend of the blog, Sol Orwell, has been an expert on nutritional supplements for many years and has consulted extensively for vitamin and supplement manufacturers. He and his colleagues have spent years compiling the most extensive database of peer-reviewed literature available, and have compiled the data into a 762 page reference guide that has a comprehensive overview of the supplement literature. It is an encyclopedic resource with background information about almost every supplement that has been studied, including herbal remedies, each graded for quality of evidence, and easily searchable by:

supplement, to view the evidence for effects, good and bad, of each supplement; and

The Atlantic Article

OK, so what evidence does Offit compile against supplements?

Central to his case is a paper that we’ve already discussed on this blog (“Around the Web; The Case of the Killer Vitamins,” October 15, 2011): the 2011 analysis of the Iowa Women’s Health Study by Jaakko Mursu and collaborators in Archives of Internal Medicine. [1] Offit highlights it in the very first sentence of his article:

On October 10, 2011, researchers from the University of Minnesota found that women who took supplemental multivitamins died at rates higher than those who didn’t.

Apart from this reference he discusses two issues:

Linus Pauling’s argument that vitamin C can prevent colds and cancer has not been supported. A history of Pauling’s romance with vitamin C occupies about two-thirds of the article, and Offit seems to think the whole idea of supplementation was originated by Pauling and persists due to his influence (“What few people realize, however, is that their fascination with vitamins can be traced back to one man,” Pauling.).

Multiple studies have shown that supplementing vitamins A and E is often harmful.

This is hardly a comprehensive case against supplementation; it only shows that a few supplements tend to be harmful or lack benefits.

Regarding vitamins A and E, we agree; they are noted in our book as nutrients that should generally not be supplemented, or should be supplemented in low doses from natural sources. For example, we recommend eating a quarter pound of liver per week for vitamin A and other nutrients.

Regarding vitamin C, that it may not prevent colds or cancer does not mean it has no benefits. A few:

Our book has more evidence for benefits of vitamin C supplementation. Many people notice improved skin, hair, nails, gums, and teeth when supplementing with vitamin C, and faster wound healing. Vitamin C needs rise dramatically in sickness and stress.

It would be easy enough to compile further evidence of benefits of supplementation. Indeed, it was not so long ago that pellagra was rampant in the US South, and beriberi in East Asia. Many foods are subject to mandatory micronutrient fortification – a form of supplementation – to prevent iodine, folate, niacin, and thiamin deficiencies. So at least one branch of the government is convinced some supplementation is desirable.

The Iowa Women’s Health Study

The study followed a large number of women in Iowa, and queried them several times about supplement use. In 1986, the baseline, the women had an average age of 62 (range of 55 to 69) and 66% were taking supplements. By 2004, the surviving women had an average age of 82 and 85% were taking supplements.

Here is the data on overall mortality vs supplement use:

“Cases” are instances of someone dying. “HR” or hazard ratio is the likelihood of dying if you supplement divided by the likelihood of dying if you don’t. Note that all the hazard ratio estimates are “adjusted.”

We can calculate the raw data from the Users and Nonusers columns. In general, supplements had no obvious effect – certainly no statistically significant effect. The fraction of Users and Nonusers who died was essentially identical. If we eliminate copper which only had 229 supplementers, the hazard ratio of supplementers averaged 99.8% that of non-supplementers – i.e., supplementers were very slightly less likely to die.

But – and this is a key point – supplement use increased with age throughout the study. Roughly, 66% of 62 year olds took supplements and 82% of 82 year olds took supplements. But mortality at age 82 is about five times higher than mortality at age 62. So the high-mortality 82 year olds were supplementing more than the low-mortality 62 year olds, but supplementers had the same mortality as non-supplementers! This indicates that with age adjustment, supplementation would have shown a clear benefit.

Did Mursu et al offer an age-adjusted analysis? No, they did not. The next column in the table is age-and-energy-adjusted. “Energy” means calories of daily food intake. But the purpose of eating is to supply our body with nutrients, and supplementing nutrients reduces appetite and energy intake. (This is discussed in Chapter 17 of our book.) Lower energy intake is associated with better health, largely because a high proportion of the elderly are diabetic: 27% of those over age 65 or older are diabetic, and 50% are diabetic or prediabetic; diabetics and prediabetics benefit from lower energy intake. By adjusting for energy, they are removing credit from the supplements for the health improvements due to reduced energy intake.

Nevertheless, after age-and-energy adjustment, we find that supplements generally decreased mortality. Nine of the fifteen supplements decreased mortality, five increased mortality. At the 95% confidence interval, five supplements decreased mortality, only one increased mortality.

Making the Elephant Wiggle His Trunk

With four parameters I can fit an elephant, and with five I can make him wiggle his trunk.

Mursu et al used multivariable adjustments with 11 parameters and 16 parameters respectively to obtain their “results.” Using so many parameters lets the investigators generate whatever results they want.

I don’t think it’s a coincidence that both multivariable adjustments substantially increased the hazard ratio of every single one of the 15 supplements. The 11-variable adjustment increased hazard ratios by an average of 7%, the 16-variable adjustment by an average of 8.2%.

Rest assured, it would have been easy enough to find multivariable adjustments that would have decreased hazard ratios for every single one of the 15 supplements by 7 or 8 percent.

I believe it verged on the unethical that the variables chosen include dangerous health conditions: diabetes, high blood pressure, and obesity. These three health conditions just happen to be conditions that are improved by supplementation.

Anyone familiar with how regression analyses work will immediately recognize the problem. The adjustment variables serve as competing explanations for changes in mortality. If supplementation decreases diabetes, high blood pressure, and obesity, and through these changes decreases mortality, the supplements will not get credit for the mortality reduction; rather the decreased diabetes, blood pressure, and obesity will get the credit.

It’s appropriate to ask: if it’s proper to include health conditions like diabetes as variables in the regression, why not include other health conditions like cancer? The likely answer: Supplementation does not generally help conditions such as cancer, so including such conditions as adjustment factors would not have made the supplements seem more harmful. Rather, by giving greater weight to diabetes and obesity – conditions supplementation benefits – it would have made supplements look more beneficial.

It is impossible to take seriously studies that provide 11- and 16-variable adjustments, with arbitrarily chosen adjustment factors and no sensitivity analysis showing how alternative choices of adjustment factors would have altered the results.

Conclusion

The great economist Ronald Coase (in his essay “How should economists choose?”) said, “If you torture the data enough, nature will always confess.”

The Mursu paper was an exercise in torturing data until it declared, “Supplements are harmful!”

The Offit piece is a polemical exercise pretending that an unsettled part of biology – our nutrient needs, and the circumstances in which food fails to meet them – is a settled subject with a simple answer.

Now, it’s quite difficult to establish the healthfulness of supplementation in general, because you can always get too much of a nutrient, nutrient needs differ among persons depending on their health and age, and whether a person will benefit from a nutrient depends on whether the rest of the diet is deficient in that nutrient. So any given supplement is going to be harmful in some circumstances, beneficial in others.

A proper scientific approach would be to try to determine the circumstances under which supplements (or dietary changes eliminating the deficiency) would be beneficial.

On Wednesday a new paper reported that higher levels of long-chain omega-3 fats (EPA, DPA, and DHA) in blood are associated with a 43% increased risk of prostate cancer and a 71% increased risk of aggressive prostate cancer. [1] This built on earlier work by the same group. [2] In a press release, the authors stated:

“We’ve shown once again that use of nutritional supplements may be harmful,” said Alan Kristal, Dr.P.H., the paper’s senior author …

“[W]e have confirmed that marine omega-3 fatty acids play a role in prostate cancer occurrence,” said corresponding author Theodore Brasky, Ph.D.

They sound confident! Is there anything to it, and should it affect our dietary advice?

Mechanisms Linking Omega-3 Fats to Cancer

In our book and on this blog, we’ve already discussed two mechanisms linking excessive omega-3 intake to cancer risk.

First, there is the issue of lipid peroxidation. Of all fatty acids, long-chain omega-3 fats are the most readily peroxidized:

Peroxidation of PUFA generates highly toxic compounds, such as aldehydes, which mutate DNA and turn proteins into advanced lipoxidation end products (ALEs). [3, 4] These lipid peroxidation products have been implicated as causal factors in cancer. [5]

So there are known mechanisms by which the long omega-3s in fish oil may promote cancer.

The Brasky et al Papers

The new study by Brasky et al measured omega-3 fat levels in plasma phospholipids. Thus, it doesn’t measure any omega-3s in cells, only omega-3s in serum particles like LDL, HDL, and VLDL; and even in those particles it excludes omega-3 fats found in triglycerides.

This is a very different biomarker than the Omega-3 Index of William Harris, which looks at the omega-3 phospholipids in red blood cell membranes. [6] This biomarker might behave quite differently than the Omega-3 Index.

The study measured plasma phospholipid omega-3s in a group of people, then followed them for 6 years or so to see who developed cancer. Here are the group averages [1]:

Statistically the most reliable data is in the no cancer vs total cancer comparison. There we find that subjects who went on to develop prostate cancer averaged 3% more DHA and 4% more EPA+DPA+DHA in plasma phospholipids than those who didn’t develop cancer.

Does This Variation Reflect Dietary Intake?

Chris Kresser kindly sent a link to an analysis of the study published at LecturePad by William Harris: “Omega-3 Fatty Acids and Risk for Prostate Cancer.” Harris tells us how to translate the plasma numbers to the corresponding Omega-3 Index numbers:

Based on experiments in our lab, the lowest quartile would correspond to an HS-Omega-3 Index of <3.16% and the highest to an Index of >4.77%).

Even the top quartile of the Brasky et al subjects had quite low omega-3 levels:

In Framingham, the mean Omega-3 Index of participants who were not taking fish oil supplements was 5.2% and for those taking supplements, it was 7.5% [7]. Both of these numbers are considerably higher than the values reported by Braskey et al., even in their highest quartile.

The trial asked its participants not to take supplements, and it looks like they drew a study population whose fish intake was much lower than that of Framingham, Massachusetts, residents.

If dietary omega-3 intake was low in all subjects and varied only slightly among participants, how do we know that this biomarker is related in any way to dietary intake? There could be other factors – genetics, oxidative environment, omega-6 fat intake, antioxidant intake, changes in the proportions of VLDL, LDL, and HDL, to name a few – that affect this biomarker.

Does High Dietary Intake Lead to More Cancer?

If high dietary intake of omega-3s caused more cancer, we would expect cultures that consume lots of fish oil to have higher prostate cancer rates. But epidemiological studies have found that high omega-3 intakes seem to be associated with low cancer rates. For instance, the Japanese eat eight times more omega-3 fatty acids than Americans and their blood levels are twice as high, yet the prostate cancer rates are only one-sixth the American rate.

Of course, there are many confounders in epidemiological studies. Harris helpfully provides a summary of clinical trials in which fish oil was provided as part of the study and cancer outcomes measured:

Although none of these studies produced a statistically significant link between omega-3 intake and cancer, incidence of cancer diagnosis or death was increased in every one of the clinical trials except the GISSI-Heart Failure study and perhaps the Origin study. A meta-analysis might find a small cancer promoting effect of omega-3s.

UPDATE: Vladimir Heiskanen points me to an interesting paper in which the effect of dietary fatty acids on cancer metastasis was examined. Colon carcinoma cells were injected into the portal vein (which leads from intestine to liver) of rats and 3 weeks later rats were sacrificed and their livers were examined for metastases. The rats were on three diets — low-fat, high omega-6 (safflower oil), high omega-3 (fish oil). The results:

At 3 weeks after tumor transplantation, the fish oil diet and the safflower oil diet had induced, respectively, 10- and 4-fold more metastases (number) and over 1000- and 500-fold more metastases (size) than were found in the livers of rats on the low-fat diet. [7]

I wish they’d used a saturated fat or monounsaturated fat diet, rather than a low-fat diet, as the control, as this would have clarified that polyunsaturates specifically promote metastasis; in the study the rats’ food was mixed with fish oil or safflower oil, greatly increasing the fat fraction and decreasing the carbohydrate, protein, and micronutrient fractions, so the control diet deviates in many respects from the high-PUFA diets. However, the results are consistent with the idea that fish oil is more cancer-promoting than the less peroxidizable safflower oil, perhaps because of the unique pro-angiogenic effects of DHA products.

Conclusion

There might be biological contexts in which omega-3 fats promote cancer.

This doesn’t mean we should refrain from eating omega-3 fats. Cardiovascular disease causes more deaths than cancer, and omega-3 fats are protective against CVD.

However, I think these studies support the PHD advice:

Eat enough oily marine fish to achieve omega-6 and omega-3 balance;

Minimize omega-6 intake so that omega-6 and omega-3 balance is achieved at the lowest possible intake of polyunsaturated fats.

All nutrients can be eaten in excess, and omega-3 fats surely fall into this category. The right amount of oily fish is probably about one to two meals per week.

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